Hydroxy substituted fused naphthyl-azoles and fused indeno-azoles and their use for the treatment of glaucoma

ABSTRACT

Hydroxy substituted fused naphthyl-azoles and fused indeno-azoles are disclosed. Also disclosed are methods for the lowering and controlling of normal or elevated intraocular pressure as well as a method for the treatment of glaucoma using compositions containing one or more of the compounds of the present invention.

[0001] This application is a divisional of U.S. patent application Ser.No. 10/231,699, filed Aug. 30, 2002, which claims the benefit of U.S.Provisional Patent Application No. 60/316,391 filed Aug. 31, 2001, andis incorporated in its entirety by reference herein.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to various indazoles and indoles.Preferably the present invention is directed to the use of substituted2-(benzo[g]indazol-1-yl)-ethylamines and1-(4H-indeno[1,2-c]pyrazol-1-yl)-1-methylethylamines. These compoundsare useful for lowering and controlling normal or elevated intraocularpressure (IOP) and for treating glaucoma.

[0003] The disease state referred to as glaucoma is characterized by apermanent loss of visual function due to irreversible damage to theoptic nerve. The several morphologically or functionally distinct typesof glaucoma are typically characterized by elevated IOP, which isconsidered to be causally related to the pathological course of thedisease. Ocular hypertension is a condition wherein intraocular pressureis elevated but no apparent loss of visual function has occurred; suchpatients are considered to be a high risk for the eventual developmentof the visual loss associated with glaucoma. If glaucoma or ocularhypertension is detected early and treated promptly with medicationsthat effectively reduce elevated intraocular pressure, loss of visualfunction or its progressive deterioration can generally be ameliorated.Drug therapies that have proven to be effective for the reduction ofintraocular pressure include both agents that decrease aqueous humorproduction and agents that increase the outflow facility. Such therapiesare in general administered by one of two possible routes, topically(direct application to the eye) or orally.

[0004] There are some individuals who do not respond well when treatedwith certain existing glaucoma therapies. There is, therefore, a needfor other topical therapeutic agents that control IOP.

[0005] Serotonergic 5-HT_(1A) agonists have been reported as beingneuroprotective in animal models and many of these agents have beenevaluated for the treatment of acute stroke among other indications.This class of compounds has been mentioned for the treatment of glaucoma(lowering and controlling IOP), see e.g., WO 98/18458 (DeSantis, et al.)and EP 0771563A2 (Mano, et al.). Osborne, et al. (Ophthalmologica, Vol.210:308-314, 1996) teach that 8-hydroxydipropylaminotetralin (8-OH-DPAT)(a 5-HT_(1A) agonist) reduces IOP in rabbits. Wang, et al. (Current EyeResearch, Vol. 16(8):769-775, August 1997, and IVOS, Vol. 39(4), S488,March, 1998) indicate that 5-methylurapidil, an α_(IA) antagonist and5-HT_(1A) agonist lowers IOP in the monkey, but due to its α_(1A)receptor activity. Also, 5-HT_(1A) antagonists are disclosed as beinguseful for the treatment of glaucoma (elevated IOP),(e.g., WO 92/0338,McLees). Furthermore, DeSai, et al. (WO 97/35579) and Macor, et al.(U.S. Pat. No. 5,578,612) relate to the use of 5-HT₁ and 5-HT_(1-like)agonists for the treatment of glaucoma (elevated IOP). Theseanti-migraine compounds are 5-HT_(1B,D,E,F) agonists, e.g., sumatriptanand naratriptan and related compounds.

[0006] It has been found that serotonergic compounds which possessagonist activity at 5-HT₂ receptors effectively lower and control normaland elevated IOP and are useful for treating glaucoma, see commonlyowned co-pending application, PCT/US99/19888, incorporated in itsentirety by reference herein. Compounds that act as agonists at 5-HT₂receptors are well known and have shown a variety of utilities,primarily for disorders or conditions associated with the centralnervous system (CNS). U.S. Pat. No. 5,494,928 relates to certain2-(indol-1-yl)-ethylamine derivatives that are 5-HT_(2C) agonists forthe treatment of obsessive compulsive disorder and other CNS derivedpersonality disorders. U.S. Pat. No. 5,571,833 relates to tryptaminederivatives that are 5-HT₂ agonists for the treatment of portalhypertension and migraine. U.S. Pat. No. 5,874,477 relates to a methodfor treating malaria using 5-HT_(2A/2C) agonists. U.S. Pat. No.5,902,815 relates to the use of 5-HT_(2A) agonists to prevent adverseeffects of NMDA receptor hypo-function. WO 98/31354 relates to 5-HT_(2B)agonists for the treatment of depression and other CNS conditions. WO00/12475 relates to indoline derivatives and WO 00/12510 and WO 00/44753relate to certain indole derivatives as 5-HT_(2B) and 5-HT_(2C) receptoragonists for the treatment of a variety of disorders of the centralnervous system, but especially for the treatment of obesity. WO 00/35922relates to certain pyrazino[1,2-a]quinoxaline derivates as 5-HT_(2C)agonists for the treatment of obsessive compulsive disorder, depression,eating disorders, and other disorders involving the CNS. WO 00/77002 andWO 00/77010 relate to certain substituted tetracyclicpyrido[4,3-b]indoles as 5-HT_(2C) agonists with utility for thetreatment of central nervous system disorders including obesity,anxiety, depression, sleep disorders, cephalic pain, and social phobiasamong others. Agonist response at the 5-HT_(2A) receptor is reported tobe the primary activity responsible for hallucinogenic activity, withsome lesser involvement of the 5-HT_(2C) receptor possible[Psychopharmacology, Vol. 121:357, 1995].

[0007] U.S. Pat. No. 5,561,150 relates to substituted2-(benzo[g]indazol-1-yl)-1-ethylamines and2-(4H-indeno[1,2-c]pyrazol-1-yl)-1-ethylamine having preferentialaffinity for the 5-HT_(2C) receptor as well as affinity for the5-HT_(2A) receptor. Further, it is mentioned that these compounds haveutility for certain central nervous system disorders of therapeuticsignificance.

[0008] U.S. Pat. No. 5,646,173 relates to certain tricyclic pyrazolederivative compounds which are identified as being 5-HT_(2C) agonistsfor the treatment of CNS diseases and are primarily directed tolipophilic analogs that have a high probability of entering the brain.Similarly, WO 98/56768 relates to tricyclic 5-HT_(2C) agonists for thetreatment of CNS diseases.

[0009] All of the patents, patent applications, and publicationsmentioned above and throughout are incorporated in their entirety byreference herein and form a part of the present application.

[0010] 5-Hydroxytryptamine (serotonin) does not cross the blood-brainbarrier and enter the brain. However, in order to increase brainserotonin levels the administration of 5-hydroxy-tryptophane can beemployed. The transport of 5-hydroxy-tryptophane into the brain readilyoccurs, and once in the brain 5-hydroxy-tryptophane is rapidlydecarboxylated to provide serotonin. Since the treatment of glaucoma ispreferably with compounds that do not enter the CNS, relatively polarcompounds that are 5-HT₂ agonists and have incorporated into theirstructure a phenolic hydroxyl group that can be considered comparable tothat of serotonin, are of particular interest.

[0011] The chemical synthesis of2-(4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethylamine has been reported [J.Heterocyclic Chem. 11, 387 (1974), Chem. Heterocycl. Compd. (Engl.Transl.) 9, 196 (1973)] with no mention of utility. The synthesis ofselected 2-(4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethylamine derivatives,such as2-(8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethylamine,has been reported [Bioorg. Med. Chem. Lett. 10, 919 (2000)]. It wassuggested that such compounds could have utility in the treatment ofepilepsy and obesity. The preparation of 1- and 2-substituted2H-indeno[1,2,3-cd]indazoles is disclosed in Belg. 718,057 (1968); thesecompounds are noted as having psychotherapeutic activity. Various ringsubstituted amides and esters of7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-carboxylic acid have beendisclosed as antagonists at 5-HT₃ receptors [U.S. Pat. No. 4,985,424].

[0012] Accordingly, there is a need to provide compounds which avoid thedisadvantages described above and which provide increased chemicalstability and a desired length of therapeutic activity, for instance, indecreasing intraocular pressure and treating glaucoma.

SUMMARY OF THE PRESENT INVENTION

[0013] A feature of the present invention is to provide novel compoundswhich are preferably 5-HT₂ agonists.

[0014] A feature of the present invention is to provide compounds whichhave increased chemical stability and which are useful in lowering andcontrolling normal or elevated intraocular pressure and/or treatingglaucoma.

[0015] Another feature of the present invention is to provide compoundswhich provide a desired level of therapeutic activity in lowering andcontrolling normal or elevated intraocular pressure and/or treatingglaucoma.

[0016] Additional features and advantages of the present invention willbe set forth in part in the description that follows, and in part willbe apparent from the description, or may be learned by practice of thepresent invention. The objectives and other advantages of the presentinvention will be realized and attained by means of the elements andcombinations particularly pointed out in the description and appendedclaims.

[0017] To achieve these and other advantages, and in accordance with thepurposes of the present invention, as embodied and broadly describedherein, the present invention relates to methods to lower and/or controlnormal or elevated intraocular pressure by administering an effectiveamount of a composition containing a compound having Formula I asdescribed below:

[0018] wherein

[0019] R¹ and R² are independently hydrogen;

[0020] R³ and R⁴ are independently chosen from hydrogen, an alkyl groupsuch as C_(1,4)alkyl, or R³, R⁴ and the carbon atom to which they areattached can form a cyclopropyl ring, or furthermore, R² and R³ togethercan be (CH₂)_(m) to form a saturated heterocycle; and when R² and R³ arepart of a heterocycle, R¹ can be hydrogen or an alkyl group such as aC_(1,4)alkyl;

[0021] R⁵ is chosen from hydrogen, halogen, or an unsubstituted orsubstituted alkyl group, such as C₁₋₄alkyl or C₁₋₄alkyl substituted withhalogen;

[0022] R⁶-R⁹ are independently chosen from hydrogen, halogen, anunsubstituted or substituted alkyl group, an unsubstituted orsubstituted alkoxy group, or hydroxyl group, such as C₁₋₄alkyl,C₁₋₄alkoxy, hydroxyl, or C₁₋₄alkyl substituted by halogen;

[0023] A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;

[0024] X is either N or CH;

[0025] R¹⁰ and R¹¹ are hydrogen, an unsubstituted or substituted alkylgroup, such as C₁₋₄alkyl, or halogen;

[0026] m is 3 or 4;

[0027] and pharmaceutically acceptable salts and solvates of thecompounds of Formula I.

[0028] In preferred aspects of the invention, at least one of R³ or R⁴is an alkyl group such as C₁₋₄alkyl. Preferably, at least one of R³ orR⁴ is a methyl group. Most preferably, R³ is a methyl group.

[0029] The present invention also relates to a method for treatingglaucoma which involves administering an effective amount of acomposition containing a compound having Formula I as described above.

[0030] The present invention further relates to the use ofpharmaceutical compositions containing at least one compound of FormulaI.

[0031] In addition, the present invention relates to compoundsrepresented by Formula I:

[0032] a) wherein R¹ is a hydrogen or a substituted or unsubstitutedalkyl group;

[0033] R² and R³ together represent (CH₂)_(m) to form a saturatedheterocycle;

[0034] R⁵ is chosen from hydrogen, halogen, or a substituted orunsubstituted alkyl group;

[0035] R⁶-R⁹ are independently chosen from hydrogen, halogen, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedalkoxy group, or hydroxyl;

[0036] A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;

[0037] X is N or CH;

[0038] R¹⁰ and R¹¹ are independently hydrogen, a substituted orunsubstituted alkyl group, or halogen;

[0039] m is 3 or 4;

[0040] or pharmaceutically acceptable salts or solvates thereof; or

[0041] b) wherein R¹ and R² are hydrogen;

[0042] R³, R⁴ and the carbon atom to which they are attached form acyclopropyl ring;

[0043] R⁵ is chosen from hydrogen, halogen, or a substituted orunsubstituted alkyl group;

[0044] R⁶-R⁹ are independently chosen from hydrogen, halogen, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedalkoxy group, or hydroxyl;

[0045] A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;

[0046] X is N or CH;

[0047] R¹⁰ and R¹¹ are independently hydrogen, a substituted orunsubstituted alkyl group, or halogen;

[0048] m is 3 or 4;

[0049] or pharmaceutically acceptable salts or solvates thereof; or

[0050] c) wherein R¹ and R² are hydrogen; or R¹ is a hydrogen or asubstituted or unsubstituted alkyl group when R² and R³ are part of aheterocycle;

[0051] R³ and R⁴ are independently chosen from hydrogen, or R³, R⁴ andthe carbon atom to which they are attached form a cyclopropyl ring, orR² and R³ together represent (CH₂)_(m) to form a saturated heterocycle;

[0052] R⁵ is chosen from hydrogen, halogen, or a substituted orunsubstituted alkyl group;

[0053] R⁶-R⁹ are independently chosen from hydrogen, halogen, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedalkoxy group, or hydroxyl;

[0054] A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;

[0055] X is N or CH;

[0056] R¹⁰ and R¹¹ are independently hydrogen, a substituted orunsubstituted alkyl group, or halogen;

[0057] m is 3 or 4; wherein at least one of R⁵, R¹⁰, or R¹¹ is a halogen

[0058] or pharmaceutically acceptable salts or solvates thereof; or

[0059] d) wherein R¹ and R² are hydrogen; or R¹ is a hydrogen or asubstituted or unsubstituted alkyl group when R² and R³ are part of aheterocycle;

[0060] R³ and R⁴ are independently chosen from hydrogen, or R³, R⁴ andthe carbon atom to which they are attached form a cyclopropyl ring, orR² and R³ together represent (CH₂)_(m) to form a saturated heterocycle;

[0061] R⁵ is chosen from hydrogen, halogen, or a substituted orunsubstituted alkyl group;

[0062] R⁶-R⁹ are independently chosen from hydrogen, halogen, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedalkoxy group, or hydroxyl;

[0063] A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;

[0064] X is CH;

[0065] R¹⁰ and R¹¹ are independently hydrogen, a substituted orunsubstituted alkyl group, or halogen;

[0066] m is 3 or 4;

[0067] or pharmaceutically acceptable salts or solvates thereof.

[0068] It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are intended to provide a further explanation ofthe present invention, as claimed.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0069] The present invention relates to a variety of compounds that areuseful according to the present invention. These compounds are generallyrepresented by the following Formula I:

[0070] wherein

[0071] R¹ and R² are independently hydrogen;

[0072] R³ and R⁴ are independently chosen from hydrogen, an alkyl groupsuch as C_(1,4)alkyl, or R³, R⁴ and the carbon atom to which they areattached can form a cyclopropyl ring, or furthermore, R² and R³ togethercan be (CH₂)_(m) to form a saturated heterocycle; and when R² and R³ arepart of a heterocycle, R¹ can be hydrogen or an unsubstituted orsubstituted alkyl group, such as a C₁₋₄alkyl;

[0073] R⁵ is chosen from hydrogen, halogen, or an unsubstituted orsubstituted alkyl group, such as C₁₋₄alkyl or C₁₋₄alkyl substituted withhalogen;

[0074] R⁶-R⁹ are independently chosen from hydrogen, halogen, anunsubstituted or substituted alkyl group, an unsubstituted orsubstituted alkoxy group, or hydroxyl group, such as C₁₋₄alkyl,C₁₋₄alkoxy, hydroxyl, or C₁₋₄alkyl substituted with halogen;

[0075] A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;

[0076] X is either N or CH;

[0077] R¹⁰ and R¹¹ are independently chosen from hydrogen, halogen, oran unsubstituted or substituted alkyl group, such as C₁₋₄alkyl;

[0078] m is 3 or 4;

[0079] and pharmaceutically acceptable salts and solvates of thecompounds of Formula I.

[0080] Preferred Compounds are:

[0081] Wherein

[0082] R¹ and R² are hydrogen;

[0083] R³ is C₁₋₄alkyl or R² and R³ together can be (CH₂)₃ to formpyrrolidine;

[0084] R⁴ is hydrogen;

[0085] R⁵ is chosen from hydrogen, halogen, C₁₋₄alkyl, or C₁₋₄alkylsubstituted with halogen;

[0086] R⁶-R⁹ are independently chosen from hydrogen, halogen, C₁₋₄alkyl,C₁₋₄alkoxy, hydroxyl, or C₁₋₄alkyl substituted with halogen;

[0087] A is CH═CH, CH₂CH₂, or CR¹⁰R¹¹; and

[0088] X is N; or pharmaceutically acceptable salts and solvates of theabove preferred compounds.

[0089] Most Preferred Compounds are:

[0090] Wherein

[0091] R¹ and R² are hydrogen;

[0092] R³ is C₁₋₄alkyl;

[0093] R⁴ is hydrogen;

[0094] R⁵ and R⁶ are independently chosen from hydrogen, halogen, orC₁₋₄alkyl;

[0095] R⁷, R⁸ and R⁹ are independently chosen from hydrogen, halogen, orhydroxyl;

[0096] A is CH═CH or CH₂CH₂; and

[0097] X is N; or pharmaceutically acceptable salts and solvates of theabove preferred compounds.

[0098] Representative Examples of Preferred Compounds of Formula I are:

[0099] 1-(2-Aminopropyl)-4,5-dihydro-2H-benzo[g]indazol-8-ol;

[0100] 1-(2-Aminopropyl)-2H-benzo[g]indazol-8-ol;

[0101] 1-(2-Aminopropyl)-2H-benzo[g]indazol-7-ol;

[0102] 2-(8-Methoxy-benzo[g]indazol-1-yl)-1-methylethylamine;

[0103] 1-(2-Aminopropyl)-1,4-dihydro-indeno[1,2-c]pyrazol-6-ol; or

[0104]1-(2-Aminopropyl)-4,4-dimethyl-1,4-dihydro-indeno[1,2-c]pyrazol-7-ol; orcombinations thereof.

[0105] It is recognized that compounds of Formula I can contain one ormore chiral centers. This invention contemplates all enantiomers,diastereomers, and mixtures thereof.

[0106] In the above definitions, the total number of carbon atoms in asubstituent group is indicated by the C_(i-j) prefix where the numbers iand j define the number of carbon atoms. This definition includesstraight chain, branched chain, and cyclic alkyl or (cyclic alkyl)alkylgroups. A substituent may be present either singly or multiply whenincorporated into the indicated structural unit. For example, thesubstituent halogen, which means fluorine, chlorine, bromine, or iodine,would indicate that the unit to which it is attached may be substitutedwith one or more halogen atoms, which may be the same or different.

[0107] In the formulas described above, the alkyl group can bestraight-chain, branched, or cyclic and the like. Halogen includes Cl,Br, F, or I. Alkoxy is understood as an alkyl group bonded through anoxygen atom.

Synthesis

[0108] The substituted 1-(benzo[g]indazol-2-yl)-1-ethylamine compoundsof Formula I can be prepared by using the procedures described in U.S.Pat. No. 5,561,150 (incorporated in its entirety by reference herein) orby the modifications of these procedures as described in Scheme 1.Hydroxymethyleneketone 2 was prepared by addition of ethyl formate tothe enolate of tetralone 1. Condensation of enal 2 with the desiredsubstituted ethylaminohydrazine furnished a mixture of two isomericN-substituted indazoles, which are separated by column chromatography.Protection of the amino group, oxidation with DDQ, and subsequentdeprotection affords amine 6.

[0109] The preferred compounds of Formula I are described in Examples 2and 4. The most preferred compound is in Example 4. Examples offormulations anticipated to be suitable for delivery of this compound tothe eye are provided.

[0110] The compounds of this invention, Formula I, can be incorporatedinto various types of ophthalmic formulations for delivery to the eye(e.g., topically, intracamerally, or via an implant). The compounds arepreferably incorporated into topical ophthalmic formulations fordelivery to the eye. The compounds may be combined withophthalmologically acceptable preservatives, viscosity enhancers,penetration enhancers, butters, sodium chloride, and water to form anaqueous, sterile ophthalmic suspension or solution. Ophthalmic solutionformulations may be prepared by dissolving a compound in aphysiologically acceptable isotonic aqueous buffer. Further, theophthalmic solution may include an ophthalmologically acceptablesurfactant to assist in dissolving the compound. Furthermore, theophthalmic solution may contain an agent to increase viscosity, such ashydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, orthe like, to improve the retention of the formulation in theconjunctival sac. Gelling agents can also be used, including, but notlimited to gellan and xanthan gum. In order to prepare sterileophthalmic ointment formulations, the active ingredient is combined witha preservative in an appropriate vehicle, such as, mineral oil, liquidlanolin, or white petrolatum. Sterile ophthalmic gel formulations may beprepared by suspending the active ingredient in a hydrophilic baseprepared from the combination of, for example, carbopol-974, or thelike, according to the published formulations for analogous ophthalmicpreparations; preservatives and tonicity agents can be incorporated.

[0111] The compounds are preferably formulated as topical ophthalmicsuspensions or solutions, with a pH of about 5 to 8. The compounds willnormally be contained in these formulations in an amount 0.01% to 5% byweight, but preferably in an amount of 0.25% to 2% by weight. Thus, fortopical presentation 1 to 2 drops of these formulations would bedelivered to the surface of the eye 1 to 4 times per day according tothe discretion of a skilled clinician.

[0112] The compounds can also be used in combination with other agentsfor treating glaucoma, such as, but not limited to, β-blockers (e.g.,timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol),carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), α1antagonists (e.g., nipradolol), α2 agonists (e.g. iopidine andbrimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandinanalogs (e.g., latanoprost, travaprost, unoprostone, and compounds setforth in U.S. Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444),“hypotensive lipids” (e.g., lumnigan and compounds set forth in U.S.Pat. No. 5,352,708), and neuroprotectants (e.g., compounds from U.S.Pat. No. 4,690,931), particularly eliprodil and R-eliprodil, as setforth in a pending application U.S. S. No. 06/203,350, and appropriatecompounds from WO 94/13275, including memantine. All of the patents,applications, and publications are incorporated in their entirety byreference herein.

[0113] The compounds of the present invention preferably function as5-HT₂ agonists and preferably do not enter the CNS. In more detail, theparticular compounds of the present invention have incorporated intotheir structure a phenolic hydroxyl group which is considered comparableto that of serotonin and thus the compounds of the present inventionpreferably do not cross the blood-brain barrier and enter the brain.Compounds having the ability to be a 5-HT₂ agonist are beneficial forcontrolling IOP as well as the treatment of glaucoma as shown inInternational Published Patent Application No. WO 00/16761, incorporatedin its entirety by reference herein.

[0114] The compounds of the present invention preferably provideincreased chemical stability and preferably achieve the desired level oftherapeutic activity which includes a lowering or controlling of IOP.

[0115] The compounds of the present invention can be used in controllingor lowering IOP in warm blooded animals including humans. Preferably, aneffective amount of the compound is administered to the patient suchthat the IOP is controlled or lowered to acceptable levels. Furthermore,the compounds of the present invention can be used to treat glaucoma inwarm blooded animals, including humans, by administering an effectiveamount of the compound to a patient in need of such treatment to treatthe glaucoma.

[0116] The following Examples are given to illustrate the preparation ofcompounds that are the subject of this invention but should not beconstrued as implying any limitations to the claims. The proton magneticresonance spectrum of each compound of the Examples was consistent withthe assigned structure.

Method 1 5-HT₂ Receptor Binding Assay

[0117] To determine the affinities of serotonergic compounds at the5-HT₂ receptors, their ability to compete for the binding of the agonistradioligand [¹²⁵I]DOI to brain 5-HT₂ receptors is determined asdescribed below with minor modification of the literature procedure[Neuropharmacology, 26, 1803 (1987)]. Aliquots of post mortem rat orhuman cerebral cortex homogenates (400 μL) dispersed in 50 mM Tris-HClbuffer (pH 7.4) are incubated with [¹²⁵I]DOI (80 pM final) in theabsence or presence of methiothepin (10 μM final) to define total andnon-specific binding, respectively, in a total volume of 0.5 ml. Theassay mixture is incubated for 1 hour at 23° C. in polypropylene tubesand the assays terminated by rapid vacuum filtration over Whatman GF/Bglass fiber filters previously soaked in 0.3% polyethyleneimine usingice-cold buffer. Test compounds (at different concentrations) aresubstituted for methiothepin. Filter-bound radioactivity is determinedby scintillation spectrometry on a beta counter. The data are analyzedusing a non-linear, iterative curve-fitting computer program [TrendsPharmacol. Sci., 16, 413 (1995)] to determine the compound affinityparameter. The concentration of the compound needed to inhibit the[¹²⁵I]DOI binding by 50% of the maximum is termed the IC₅₀ or K_(i)value.

Method 2 5-HT₂ Functional Assay: [Ca²⁺]_(i) Mobilization

[0118] The receptor-mediated mobilization on intracellular calcium([Ca²⁺]_(i)) was studied using the Fluorescence Imaging Plate Reader(FLIPR) instrument. Rat vascular smooth muscle cells, A7r5, were grownin a normal media of DMEM/10% FBS and 10 μg/mL gentamycin. Confluentcell monolayers were trypsinized, pelleted, and re-suspended in normalmedia. Cells were seeded in a 50 μL volume at a density of 20,000cells/well in a black wall, 96-well tissue culture plate and grown for 2days.

[0119] On the day of the experiment, one vial of FLIPR Calcium Assay Kitdye was re-suspended in 50 mL of a FLIPR buffer consisting of Hank'sBalanced Salt Solution (HBSS), 20 mM HEPES, and 2.5 mM probenecid, pH7.4. Cells were loaded with the calcium-sensitive dye by addition of anequal volume (50 μL) to each well of the 96-well plate and incubatedwith dye for 1 h at 23° C.

[0120] Typically, test compounds were stored at 25 μM in 50% DMSO/50%Ethanol solvent. Compounds were diluted 1:50 in 20% DMSO/20% ethanol.For “hit” screening, compounds were further diluted 1:10 in FLIPR bufferand tested at a final concentration of 10 μM. For dose-responseexperiments, compounds were diluted 1:50 in FLIPR buffer and seriallydiluted 1:10 to give a 5- or 8-point dose-response curve.

[0121] The compound plate and cell plate were placed in the FLIPRinstrument. At the beginning of an experimental run, a signal test wasperformed to check the basal fluorescence signal from the dye-loadedcells and the uniformity of the signal across the plate. The basalfluorescence was adjusted between 8000-12000 counts by modifying theexposure time, the camera F-stop, or the laser power. Instrumentsettings for a typical assay were the following: laser power 0.3-0.6 W,camera F-stop F/2, and exposure time 0.4 sec. An aliquot (25 μL) of thetest compound was added to the existing 100 μL dye-loaded cells at adispensing speed of 50 μL/sec. Fluorescence data were collected inreal-time at 1.0 sec intervals for the first 60 sees and at 6.0 secintervals for an additional 120 secs. Responses were measured as peakfluorescence intensity minus basal and where appropriate were expressedas a percentage of a maximum 5-HT-induced response. When the compoundswere tested as antagonists against 10 μM 5-HT, they were incubated withthe cells for 15 minutes prior to the addition of 5-HT.

[0122] The above procedures were used to generate the data shown inTable 1. TABLE 1 5-HT₂ Receptor Binding and Functional Data EfficacyCompound IC₅₀, nM EC₅₀, nM (E_(max), %) Example 2 1.15 103 46 Example 31.50 285 61 Example 4 2.10 211 79 Example 5 5.0 328 64 DOI 0.33 30.2 315-HT 0.941 80 107

EXAMPLE 11-(8-Methoxy-4,5-dihydro-benzo[g]indazol-2-yl)-1-methylethylamineDihydrochloride

[0123] Step A:1-(8-Methoxy-4,5-dihydro-benzo[g]indazol-1-yl)-1-methylethylamine

[0124] To a solution of2-hydroxymethylene-7-methoxy-3,4-dihydro-2H-naphthalen-1-one (0.37 g,1.8 mmol) in ethanol (15 mL) was added 2-hydrazino-1-methylethylamine(0.16 g, 1.8 mmol) and 1 N HCl (2 mL of a 1:1 mixture of methanol andethanol). This solution was heated at reflux temperature for 6 h, cooledto 23° C., and stirred for an additional 16 h. The reaction mixture wasevaporated to a crude product which was purified by chromatography(silica, gradient, 5% to 10% methanol in dichloromethane) to give an oil(0.19 g, 40%): R_(f)=0.43 (silica, 10% methanol in dichloromethane); ¹HNMR (CDCl₃) δ 7.37 (d, J=2.6 Hz, 1H), 7.20 (s, 1H), 7.12 (d, J=8.2 Hz,1H), 6.75 (dd, J=8.2, 2.6 Hz, 1H), 4.12 (dd, J=13.6, 4.2 Hz, 1H), 3.9(m, 1H), 3.88 (s, 3H), 3.5 (bs, 2H), 2.88 (t, J=6.2 Hz, 2H), 2.71 (t,J=6.2 Hz, 2H), 1.14 (d, J=6.4 Hz, 3H). The 2-substituted regioisomeralso formed during the cyclization reaction was also isolated (0.11 g,24%).

[0125] Step B: 1-(8-Methoxy-4,5-dihydro-benzo[g]indazol-1-yl)-1-methylethylamine Hydrochloride

[0126] The product from Step A (0.030 g, 0.12 mmol) was dissolved in 0.1N HCl and the solution was concentrated to give a white solid (0.021 g,53%): ¹H NMR (CDCl₃) δ 7.50 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.07 (d,J=2.4 Hz, 1H), 6.94 (dd, J=8.4, 2.4 Hz, 1H), 4.7 (m, 2H), 3.86 (m, 1H),3.83 (s, 3H), 2.78 (t, J=7.2 Hz, 2H), 2.57 (m, 2H) 1.24 (d, J=6.6 Hz,3H); MS m/z 258 [M+H]⁺, 241, 201. Analysis. Calculated forC₁₅H₁₉N₃O.2HCl.0.25H₂O: C, 53.82; H, 6.47; N, 12.55. Found: C, 53.86; H,6.73; N, 12.51.

EXAMPLE 2 1-(2-Aminopropyl)-4,5-dihydro-1H-benzo[g]indazol-8-olDihydrochloride

[0127] To a solution of the product of Step A of Example 1 (0.020 g,0.78 mmol) in 1,2-dichloroethane (10 mL) was added borontribromide-dimethylsulfide (1.0 mL, 1.0 mmol), and the solution heatedat reflux temperature for 24 hr. The solution was allowed to cool toambient temperature and the reaction was quenched by the addition ofaqueous NaHCO₃; this mixture was extracted with chloroform (2×25 mL).The combined extracts were dried (NaSO₄), filtered, and evaporated to acrude product which was purified by chromatography (silica, gradient,10% to 20% methanol in dichloromethane) to provide an oil (0.032 g,15%). Treatment of the free base with 0.5 N HCl followed byconcentration afforded the hydrochloride salt (0.010 g, 24%): ¹H NMR(D₂O) δ 7.56 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H),6.88 (dd, J=7.8, 2.4 Hz, 1H), 4.70 (m, 1H), 3.9 (m, 1H), 2.83 (m, 2H),2.67 (m, 2H), 1.31 (d, J=7.2 Hz, 3H); MS m/z: 244 [M+H]⁺, 187. Analysis.Calculated for C₁₄H₁₇N₃O.2HCl.1.4H₂O: C, 49.24; H, 6.44; N, 12.31.Found: C, 49.19; H, 6.24; N, 12.41.

EXAMPLE 3 1-(8-Methoxy-benzo[g]indazol-2-yl)-1-methylethylamineDihydrochloride

[0128] Step A:[1-(8-Methoxy-4,5-dihydro-benzo[g]indazol-1-yl)-1-methylethyl]-carbamicAcid 9H-fluoren-9-ylmethyl Ester

[0129] The crude product from Step A of Example 1 (0.2 g, 0.8 mmol) wasdissolved in a 4:1 mixture of 1,4-dioxane and water (5 mL), and NaHCO₃(0.42 g, 5.0 mmol) was added followed by 9-fluorenyl-methylchloroformate(0.26 g, 1.0 mmol), and the mixture stirred at 23° C. for 16 hr. Themixture was poured into dilute aqueous NaHCO₃ and extracted with ether(2×20 mL). The combined extracts were dried (MgSO₄), filtered andconcentrated to a residue which was purified by chromatography (silica,gradient, 20% to 50% ethyl acetate in hexanes) to give an oil (0.10 g,26%): ¹H NMR MR (CDCl₃) δ 7.75 (d, J=6 Hz, 2H), 7.56 (d, J=6 Hz, 2H),7.4-7.1 (m, 7H), 6.76 (dd, J=8, 2 Hz, 1H), 5.6 (bs, 1H), 4.53 (m, 1H),4.2-4.0 (m, 5H), 3.83 (s, 3H), 2.79 (t, J=8 Hz, 2H), 2.67 (t, J=8 Hz,2H), 1.2 (m, 3H); MS m/z: 480 [M+H]⁺, 284, 258, 201, 179.

[0130] Step B:[1-(8-Methoxy-benzo[g]indazol-1-yl)-1-methylethyl]-carbamic Acid9H-fluoren-9-ylmethyl Ester

[0131] To a solution of the product from Step A (0.08 g, 0.17 mmol) in1,4-dioxane (10 mL) was added DDQ (0.08 g, 0.34 mmol). The solution wasstirred at 23° C. for 3 hr and poured into saturated aqueous NaHCO₃ andthis mixture was extracted with ether (2×20 mL). The combined extractswere washed with aqueous NaHCO₃, dried (MgSO₄), and evaporated to acrude product., which was purified by chromatography (silica, 40% ethylacetate in hexanes) to obtain an oil (0.045 g, 55%): MS m/z: 478 [M+H]⁺.

[0132] Step C: 1-(8-Methoxy-benzo[g]indazol-1-yl)-1-methyethylamineDihydrochloride

[0133] A solution of the product from Step B (0.045 g, 0.094 mmol) in amixture of piperidine in DMF (1:4, 5 mL) was stirred for 5 min at 23°C., poured into a saturated aqueous solution of NaHCO₃ and extractedwith ethyl acetate (2×20 mL). The combined extracts were dried (NaSO₄),filtered, and concentrated to a crude product which was purified bychromatography (silica, gradient, 4% to 10% methanol in dichloromethane)to furnish an oil (0.008 g, 71%). The free base was dissolved in 0.1 Naqueous HCl (1 mL) and the solution concentrated to give thedihydrochloride as a white solid (0.0043 g, 34%): ¹H NMR (CD₃OD) δ 8.17(s, 1H), 8.00 (d, J=910 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.64 (d, J=8.6Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.4 (d, J=9 Hz, 1H), 5.23 (dd, J=15.2,4.6 Hz, 1H), 5.06 (dd, J=15.2, 8.2 Hz, 1H), 4.1 (m, 1H), 4.08 (s, 3H),1.49 (d, J=6.6 Hz, 3H); MS m/z: 256 [M+H]⁺, 199.

EXAMPLE 4 1-(2-Aminopropyl)-2H-benzo[g]indazol-7-ol

[0134] Step A:2-(7-Methoxy-4,5-dihydrobenzo[g]indazol-1-yl)-1-methylethylamine.

[0135] To a solution of 2-hydroxymethylene-6-methoxy-1-tetralone (3.3 g,16 mmol) in ethanol (10 mL) was added a 1 N solution of HCl in methanol(20 mL) followed by 2-aminopropyl-1-hydrazine (1.78 g, 20 mmol). Thismixture was treated in the manner described in Step A of Example 1 tofurnish a pale yellow oil (0.60 g, 15%): ¹H NMR (CDCl₃) δ 7.51 (d, J=8.4Hz, 1H), 7.35 (s, 1H), 6.87 (d, J=1.8 Hz, 1H), 6.82 (dd, J=8.4 Hz, 1.8Hz, 1H), 4.34 (dd, J=13.8, 4.8 Hz, 1H), 4.20 (dd, J=13.8, 8.4 Hz, 1H),3.83 (s, 3H), 3.55 (m, 1H), 2.86 (t, J=7.8 Hz, 2H), 2.67 (dd, J=7.8, 6.0Hz, 2H), 1.17 (d, J=6.6 Hz, 3H); MS m/z 258 [M+H]⁺.

[0136] Step B:[1-(7-Methoxy-4,5-dihydro-benzo[g]indazol-1-yl)-1-methylethyl]-carbamicAcid 9H-fluoren-9-ylmethyl Ester.

[0137] To a solution of the product of Step A (0.34 g, 1.3 mmol) in amixture of 1,4-dioxane (20 mL) and water (2 mL) containing NaHCO₃ (0.84g, 10 mmol) was added FMOCCl (0.52 g, 2.0 mmol) followed by stirring at23° C. for 16 h. The reaction mixture was poured into aqueous NaHCO₃ andextracted with ethyl acetate (2×20 mL). The combined extracts were dried(MgSO₄), and concentrated to a residue, which was purified bychromatography (silica, 40% ethyl acetate in hexanes) to give an oil(0.11 g, 18%): ¹H NMR (CDCl₃) δ 7.8 (m, 3H), 7.6 (m, 3H), 7.4 (m, 2H),7.2 (m, 3H), 6.8 (m, 2H), 4.4-4.1 (bm, 10H), 3.8 (d, 3H), 2.9-2.6 (m,4H), 1.3 (m, 3H); MS m/z 480 [M+H]⁺.

[0138] Step C:[1-(7-Methoxy-benzo[g]indazol-1-yl)-1-methylethyl]-carbamic Acid9H-fluoren-9-ylmethyl Ester.

[0139] To a solution of the product from Step B (0.11 g, 0.23 mmol) in1,4-dioxane (10 mL) was added DDQ (0.19 g, 0.8 mmol) and the solutionstirred at 23° C. for 72 h. The solution was poured into aqueous NaHCO₃and the mixture was extracted with ethyl acetate (2×20 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated to a residue, whichwas purified by chromatography (silica, 25% ethyl acetate in hexanes) togive an oil (0.1 g, 91%): ¹H NMR (CDCl₃) δ 8.5 (bs, 1H), 8.01 (s, 1H),7.75 (d, J=6 Hz, 2H), 7.63 (d, J=12 Hz, 1H), 7.5 (bs, 1H), 7.4 (m, 3H),7.3-7.2 (m, 5H), 5.2 (m, 1H), 5.0 (m, 1H), 4.75 (m, 1H), 4.4-4.3 (m,2H), 4.1 (m, 1H), 3.93 (s, 3H), 1.21 (t, J=6 Hz, 3H); MS m/z 478 [M+H]⁺.

[0140] Step D: 2-(7-Methoxy-benzo[g]indazol-1-yl)-1-methylethylamine.

[0141] A solution of piperidine in DMF (1:4, 5 mL) was added to theproduct of Step C (0.1 g, 0.2 mmol) and the solution was stirred for 5minutes at 23° C., poured into aqueous NaHCO₃, and extracted with ethylacetate (2×20 mL). The combined extracts were dried (MgSO₄) andconcentrated to a residue, which was purified by chromatography (silica,gradient, 3 to 10% methanol in dichloromethane) to give an oil (0.035 g,64%): 1H NMR (CDCl₃) δ 8.27 (d, J=9.0 Hz, 1H), 8.01 (s, 1H), 7.64 (d,J=9.0 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.26 (m,1H), 4.76 (dd, J=14.4, 4.8 Hz, 1H), 4.63 (dd, J=14.4, 8.4 Hz, 1H), 3.96(s, 3H), 3.67 (m, 1H), 1.25 (d, J=6.0 Hz, 3H); MS m/z 256 [M+H]⁺.

[0142] Step E: 1-(2-Aminopropyl)-1H-benzo[g]indazol-7-ol

[0143] To a solution of the product from Step D (26 mg, 0.1 mmol) in1,2-dichloroethane (16 mL) was added boron tribromide-methylsulfidecomplex (1.0 M, 1.0 mL, 1.0 mmol) and the solution stirred at reflux for72 h. The solution was poured into aqueous NaHCO₃, and extracted withethyl acetate (2×20 mL). The combined extracts were dried (MgSO₄)concentrated to a residue, which was purified by chromatography (silica,gradient, 10 to 25% methanol in dichloromethane) to furnish a solid (8mg, 32%): ¹H NMR (CDCl₃) δ 8.30 (d, J=9.0 Hz, 1H), 7.99 (s, 1H), 7.60(d, J=8.4 Hz, 1H), 7.35 (d, J=9.0 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.21(dd, J=9.0, 2.4 Hz, 1H), 3.6 (m, 1H), 3.3 (m, 2H), 1.25 (d, J=6.6 Hz,3H); MS m/z 242 [M+H]⁺.

EXAMPLE 5 1-(2-Aminopropyl)-1,4-dihydro-indeno[1,2-c]pyrazol-6-ol

[0144] Step A: 2-Hydroxymethylene-5-methoxy-1-indanone

[0145] To a mixture of sodium methoxide (1.2 g, 22 mmol) in THF (20 mL)was added ethyl formate (1.6 g, 22 mmol) and 5-methoxy-1-indanone (3.24g, 19.7 mmol) and the mixture stirred for 16 h at 23° C. The reactionmixture was added to aqueous HCl (0.1 N) and extracted with a mixture(1:1) of ethyl acetate and ether (2×20 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated to a residue, which waspurified by chromatography (silica, 40% ethyl acetate in hexanes) togive an oil (2.6 g, 69%): ¹H NMR (CDCl₃) δ 7.81 (d, J=9.6 Hz, 1H), 7.47(s, 1H), 7.00 (m, 2H), 3.94 (s, 3H), 3.9 (m, 2H); MS m/z 191 [M+H]⁺.

[0146] Step B:2-(6-Methoxy-4H-indeno[1,2-c]pyrazol-1-yl)-1-methylethylamine

[0147] To a solution of the product from Step A (1.9 g, 10 mmol) inethanol (20 mL) was added a 1 N solution of HCl in a 1:1 mixture ofmethanol and ethanol followed by 2-aminopropylhydrazine (0.9 g, 10 mmol)and the solution was heated to reflux for 16 h. The solution was allowedto cool, poured into aqueous NaHCO₃, extracted with ethyl acetate (2×20mL), dried (Na₂SO₄) and concentrated. The crude material was taken up in0.1 N HCl and washed with ether (2×20 mL), basified by the addition ofNaHCO₃ and extracted with ethyl acetate (2×20 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated to a residue, which waspurified by chromatography (silica, 10% methanol in dichloromethane) tofurnish an oil (0.48 g, 20%); MS m/z 244 [M+H]⁺.

[0148] Step C:[1-(6-Methoxy-4H-indeno[1,2-c]pyrazol-1-yl)-1-methylethyl]-carbamic Acid9H-fluoren-9-ylmethyl Ester

[0149] To a mixture of the product of Step B (0.24 g, 1.0 mmol), NaHCO₃(1 g, 12 mmol),1,4-dioxane (10 mL), and water (2 mL) was added FMOCCl (1g, 3.7 mmol). The mixture was stirred for 14 h at 23° C., then pouredinto aqueous NaHCO₃, extracted with ethyl acetate (2×20 mL), dried(MgSO₄) and concentrated to a residue, which was purified bychromatography (silica, 35% ethyl acetate in hexanes) to afford an oil(0.23 g, 50%): ¹H NMR (CDCl₃) δ 7.75 (d, J=6 Hz, 2H), 7.5 (m, 3H), 7.43(s, 1H), 7.37 (m, 2H), 7.27 (m, 2H), 7.04 (s, 1H), 6.85 (m, 1H), 5.4(bs, 1H), 4.5-4.3 (m, 4H), 4.2 (s, 1H), 4.1 (s, 1H), 3.78 (s, 3H), 3.53(s, 2H), 1.23 (m, 3H); MS m/z 466 [M+H]⁺.

[0150] Step D:2-(6-Methoxy-4H-indeno[1,2-c]pyrazol-1-yl)-1-methylethylamine

[0151] The product from Step C (0.23 g, 0.5 mmol) was dissolved in amixture of piperidine and DMF (1:4, 5 mL). The solution was stirred for10 minutes, poured into aqueous NaHCO₃, extracted with ethyl acetate(2×20 mL), dried (Na₂SO₄) and concentrated. The crude product waspurified by chromatography (silica, 10% methanol in dichloromethane) togive an oil (0.095 g, 78%): ¹H NMR (CDCl₃) δ 7.44 (d, J=7.8 Hz, 2H),7.41 (s, 1H), 7.08 (d, J=1.8 Hz, 1H), 6.88 (dd, J=7.8, 1.8 Hz, 1H), 4.30(dd, J=7.8, 4.8 Hz, 1H), 4.18 (dd, J=7.8, 4.8 Hz, 1H), 3.85 (s, 3H),3.55 (m, 2H), 3.54 (s, 2H), 1.23 (m, 3H); MS m/z 244 [M+H]⁺.

[0152] Step E: 1-(2-Aminopropyl)-1,4-dihydro-indeno[1,2-c]pyrazol-6-ol

[0153] To a solution of the product from Step D (0.56 g, 0.23 mmol) in1,2-dichloroethane (10 mL) was added boron tribromide-methylsulfidecomplex in THF solution (1.0M, 0.5 mL, 0.5 mmol) and the solution heatedto reflux for 16 h. The solution was allowed to cool, poured intoaqueous NaHCO₃, extracted with chloroform (2×20 mL), dried (Na₂SO₄) andconcentrated. The crude product was purified by chromatography (silica,20% methanol in dichloromethane) to give a solid (0.007 g, 13%): ¹H NMR(CDCl₃) δ7.39 (m, 2H), 7.00 (s, 1H), 6.79 (dd, J=8.4, 2.4 Hz, 1H), 4.30(dd, J=13.8, 4.8 Hz, 1H), 4.14 (dd, J=13.8, 7.8 Hz, 1H), 3.55 (m, 1H),3.48 (bm, 4H), 1.19 (d, J=6.6 Hz, 3H); MS m/z 230 [M+H]⁺.

[0154] Other embodiments of the present invention will be apparent tothose skilled in the art from consideration of the present specificationand practice of the present invention disclosed herein. It is intendedthat the present specification and examples be considered as exemplaryonly with a true scope and spirit of the invention being indicated bythe following claims and equivalents thereof.

What is claimed is:
 1. A method for the treatment of glaucoma comprisingadministering to a patient a pharmaceutically effective amount of acomposition comprising at least one compound of Formula I:

wherein R¹ and R² are hydrogen; or R¹ is a hydrogen or a substituted orunsubstituted alkyl group when R² and R³ are part of a heterocycle; R³and R⁴ are independently chosen from hydrogen, an alkyl group, or R³, R⁴and the carbon atom to which they are attached form a cyclopropyl ring,or R² and R³ together represent (CH₂)_(m) to form a saturatedheterocycle; R⁵ is chosen from hydrogen, halogen, or a substituted orunsubstituted alkyl group; R⁶-R⁹ are independently chosen from hydrogen,halogen, a substituted or unsubstituted alkyl group, a substituted orunsubstituted alkoxy group, or hydroxyl; A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;X is N or CH; R¹⁰ and R¹¹ are independently hydrogen, a substituted orunsubstituted alkyl group, or halogen; m is 3 or 4; or pharmaceuticallyacceptable salts or solvates thereof.
 2. The method of claim 1, whereinR¹ and R² are hydrogen; or R¹ is a hydrogen or a C_(1,4)alkyl group whenR² and R³ are part of a heterocycle; R³ and R⁴ are independently chosenfrom hydrogen, C_(1,4)alkyl, or R³, R⁴ and the carbon atom to which theyare attached form a cyclopropyl ring, or R² and R³ together represent(CH₂)_(m) to form a saturated heterocycle; R⁵ is chosen from hydrogen,halogen, C_(1,4)alkyl, or C_(1,4)alkyl substituted with halogen; R⁶-R⁹are independently chosen from hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxyl, or C₁₋₄ alkyl substituted with halogen; A is CH₂CH₂,CH═CH, or CR¹⁰R¹¹; X is N or CH; R¹⁰ and R¹¹ are independently chosenfrom hydrogen, C₁₋₄alkyl, or halogen; m is 3 or 4; or pharmaceuticallyacceptable salts and solvates thereof.
 3. The method of claim 1, whereinsaid R² and R³ form a saturated (CH₂)_(m) heterocycle or said R³ and R⁴together form a cyclopropyl ring.
 4. The method of claim 1, wherein R¹and R² are hydrogen; R³ is C₁₋₄alkyl or R² and R³ together is (CH₂)₃ toform pyrrolidine; R⁴ is hydrogen; R⁵ is chosen from hydrogen, halogen,C₁₋₄alkyl, or C₁₋₄alkyl substituted by halogen; R⁶-R⁹ are independentlychosen from hydrogen, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxyl, orC₁₋₄alkyl substituted with halogen; A is CH═CH or CH₂CH₂; and X is N; orpharmaceutically acceptable salts and solvates thereof.
 5. The method ofclaim 1, wherein: R¹ and R² are hydrogen; R³ is C₁₋₄alkyl; R⁴ ishydrogen; R⁵ is chosen from hydrogen or C₁₋₄alkyl; R⁶ and R⁷ arehydrogen, halogen, or C₁₋₄alkyl; R⁸ and R⁹ are independently chosen fromhydrogen, halogen, or hydroxyl; A is CH═CH or CH₂CH₂; and X is N; orpharmaceutically acceptable salts and solvates thereof.
 6. The method ofclaim 1, wherein said X is N.
 7. The method of claim 1, wherein said Xis CH.
 8. The method of claim 1, wherein said compound is:1-(2-Aminopropyl)-4,5-dihydro-2H-benzo[g]indazol-8-ol;1-(2-Aminopropyl)-2H-benzo[g]indazol-8-ol;1-(2-Aminopropyl)-2H-benzo[g]indazol-7-ol;2-(8-Methoxy-benzo[g]indazol-1-yl)-1-methylethylamine;1-(2-Aminopropyl)-1,4-dihydro-indeno[1,2-c]pyrazol-6-ol; or1-(2-Aminopropyl)-4,4-dimethyl-2,4-dihydro-indeno[1,2-c]pyrazol-7-ol; orcombinations thereof.
 9. A method of controlling normal or elevatedintraocular pressure comprising administering to a patient apharmaceutically effective amount of a composition comprising at leastone compound of Formula I:

wherein R¹ and R² are hydrogen; or R¹ is a hydrogen or a substituted orunsubstituted alkyl group when R² and R³ are part of a heterocycle; R³and R⁴ are independently chosen from hydrogen, C₁₋₄alkyl, or R³, R⁴ andthe carbon atom to which they are attached form a cyclopropyl ring, orR² and R³ together represent (CH₂)_(m) to form a saturated heterocycle;R⁵ is chosen from hydrogen, halogen, or a substituted or unsubstitutedalkyl group; R⁶-R⁹ are independently chosen from hydrogen, halogen, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedalkoxy group, or hydroxyl; A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹; X is N or CH;R¹⁰ and R¹¹ are independently hydrogen, a substituted or unsubstitutedalkyl group, or halogen; m is 3 or 4; or pharmaceutically acceptablesalts or solvates thereof.
 10. The method of claim 9, wherein R¹ and R²are hydrogen; or R¹ is a hydrogen or a C₁₋₄alkyl group when R² and R³are part of a heterocycle; R³ and R⁴ are independently chosen fromhydrogen, C₁₋₄alkyl, or R³, R⁴ and the carbon atom to which they areattached form a cyclopropyl ring, or R² and R³ together represent(CH₂)_(m) to form a saturated heterocycle; R⁵ is chosen from hydrogen,halogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with halogen; R⁶-R⁹ areindependently chosen from hydrogen, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy,hydroxyl, or C₁₋₄ alkyl substituted with halogen; A is CH₂CH₂, CH═CH, orCR¹⁰R¹¹; X is N or CH; R¹⁰ and R¹¹ are independently hydrogen,C₁₋₄alkyl, or halogen; m is 3 or 4; or pharmaceutically acceptable saltsand solvates thereof.
 11. The method of claim 9, wherein said R² and R³form a saturated (CH₂)_(m) heterocycle or said R³ and R⁴ together form acyclopropyl ring.
 12. The method of claim 9, wherein R¹ and R² arehydrogen; R³ is C₁₋₄alkyl or R² and R³ together is (CH₂)₃ to formpyrrolidine; R⁴ is hydrogen; R⁵ is chosen from hydrogen, halogen,C₁₋₄alkyl, or C₁₋₄alkyl substituted by halogen; R⁶-R⁹ are independentlychosen from hydrogen, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxyl, orC₁₋₄alkyl substituted with halogen; A is CH═CH or CH₂CH₂; and X is N; orpharmaceutically acceptable salts and solvates thereof.
 13. The methodof claim 9, wherein: R¹ and R² are hydrogen; R³ is C₁₋₄alkyl; R⁴ ishydrogen; R⁵ is chosen from hydrogen or C₁₋₄alkyl; R⁶ and R⁷ arehydrogen, halogen, or C₁₋₄alkyl; R⁸ and R⁹ are independently chosen fromhydrogen, halogen, or hydroxyl; A is CH═CH or CH₂CH₂; and X is N; orpharmaceutically acceptable salts and solvates thereof.
 14. The methodof claim 9, wherein said X is N.
 15. The method of claim 9, wherein saidX is CH.
 16. The method of claim 9, wherein said compound is:1-(2-Aminopropyl)-4,5-dihydro-2H-benzo[g]indazol-8-ol;1-(2-Aminopropyl)-2H-benzo[g]indazol-8-ol;1-(2-Aminopropyl)-2H-benzo[g]indazol-7-ol; 2-(8-Methoxy-benzo[g]indazol-1-yl)-1-methylethylamine;1-(2-Aminopropyl)-1,4-dihydro-indeno[1,2-c]pyrazol-6-ol; or1-(2-Aminopropyl)-4,4-dimethyl-2,4-dihydro-indeno[1,2-c]pyrazol-7-ol; orcombinations thereof.
 17. A method to block or bind to serotoninreceptors comprising administering an effective amount of a compositioncomprising at least one compound of Formula I:

wherein R¹ and R² are hydrogen; or R¹ is a hydrogen or a substituted orunsubstituted alkyl group when R² and R³ are part of a heterocycle; R³and R⁴ are independently chosen from hydrogen, an alkyl group, or R³, R⁴and the carbon atom to which they are attached form a cyclopropyl ring,or R² and R³ together represent (CH₂)_(m) to form a saturatedheterocycle; R⁵ is chosen from hydrogen, halogen, or a substituted orunsubstituted alkyl group; R⁶-R⁹ are independently chosen from hydrogen,halogen, a substituted or unsubstituted alkyl group, a substituted orunsubstituted alkoxy group, or hydroxyl; A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;X is N or CH; R¹⁰ and R¹¹ are independently hydrogen, a substituted orunsubstituted alkyl group, or halogen; m is 3 or 4; or pharmaceuticallyacceptable salts or solvates thereof.
 18. The method of claim 17,wherein R¹ and R² are hydrogen; or R¹ is a hydrogen or a C₁₋₄alkyl groupwhen R² and R³ are part of a heterocycle; R³ and R⁴ are independentlychosen from hydrogen, C₁₋₄alkyl, or R³, R⁴ and the carbon atom to whichthey are attached form a cyclopropyl ring, or R² and R³ togetherrepresent (CH₂)_(m) to form a saturated heterocycle; R⁵ is chosen fromhydrogen, halogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with halogen;R⁶-R⁹ are independently chosen from hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxyl, or C₁₋₄ alkyl substituted with halogen; A is CH₂CH₂,CH═CH, or CR¹⁰R¹¹; X is N or CH; R¹⁰ and R¹¹ are independently hydrogen,C₁₋₄alkyl, or halogen; m is 3 or 4; or pharmaceutically acceptable saltsand solvates thereof.
 19. The method of claim 17, wherein said R² and R³form a saturated (CH₂)_(m) heterocycle or said R³ and R⁴ together form acyclopropyl ring.
 20. The method of claim 17, wherein R¹ and R² arehydrogen; R³ is C₁₋₄alkyl or R² and R³ together is (CH₂)₃ to formpyrrolidine; R⁴ is hydrogen; R⁵ is chosen from hydrogen, halogen,C₁₋₄alkyl, or C₁₋₄alkyl substituted by halogen; R⁶-R⁹ are independentlychosen from hydrogen, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxyl, orC₁₋₄alkyl substituted with halogen; A is CH═CH or CH₂CH₂; and X is N; orpharmaceutically acceptable salts and solvates thereof.
 21. The methodof claim 17, wherein: R¹ and R² are hydrogen; R³ is C₁₋₄alkyl; R⁴ ishydrogen; R⁵ is chosen from hydrogen or C₁₋₄alkyl; R⁶ and R⁷ arehydrogen, halogen, or C₁₋₄alkyl; R⁸ and R⁹ are independently chosen fromhydrogen, halogen, or hydroxyl; A is CH═CH or CH₂CH₂; and X is N; orpharmaceutically acceptable salts and solvates thereof.
 22. The methodof claim 17, wherein said X is N.
 23. The method of claim 17, whereinsaid X is CH.
 24. The method of claim 17, wherein said compound is:1-(2-Aminopropyl)-4,5-dihydro-2H-benzo[g]indazol-8-ol;1-(2-Aminopropyl)-2H-benzo[g]indazol-8-ol;1-(2-Aminopropyl)-2H-benzo[g]indazol-7-ol;2-(8-Methoxy-benzo[g]indazol-1-yl)-1-methylethylamine;1-(2-Aminopropyl)-1,4-dihydro-indeno[1,2-c]pyrazol-6-ol; or1-(2-Aminopropyl)-4,4-dimethyl-2,4-dihydro-indeno[1,2-c]pyrazol-7-ol; orcombinations thereof.
 25. A compound represented by Formula I:

a) wherein R¹ is a hydrogen or a substituted or unsubstituted alkylgroup; R² and R³ together represent (CH₂)_(m) to form a saturatedheterocycle; R⁵ is chosen from hydrogen, halogen, or a substituted orunsubstituted alkyl group; R⁶-R⁹ are independently chosen from hydrogen,halogen, a substituted or unsubstituted alkyl group, a substituted orunsubstituted alkoxy group, or hydroxyl; A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;X is N or CH, R¹⁰ and R¹¹ are independently hydrogen, a substituted orunsubstituted alkyl group, or halogen; m is 3 or 4; or pharmaceuticallyacceptable salts or solvates thereof; or b) wherein R¹ and R² arehydrogen; R³, R⁴ and the carbon atom to which they are attached form acyclopropyl ring; R⁵ is chosen from hydrogen, halogen, or a substitutedor unsubstituted alkyl group; R⁶-R⁹ are independently chosen fromhydrogen, halogen, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted alkoxy group, or hydroxyl; A is CH₂CH₂,CH═CH, or CR¹⁰R¹¹; X is N or CH; R¹⁰ and R¹¹ are independently hydrogen,a substituted or unsubstituted alkyl group, or halogen; m is 3 or 4; orpharmaceutically acceptable salts or solvates thereof; or c) wherein R¹and R² are hydrogen; or R¹ is a hydrogen or a substituted orunsubstituted alkyl group when R² and R³ are part of a heterocycle; R³and R⁴ are independently chosen from hydrogen, an alkyl group, or R³, R⁴and the carbon atom to which they are attached form a cyclopropyl ring,or R² and R³ together represent (CH₂)_(m) to form a saturatedheterocycle; R⁵ is chosen from hydrogen, halogen, or a substituted orunsubstituted alkyl group; R⁶-R⁹ are independently chosen from hydrogen,halogen, a substituted or unsubstituted alkyl group, a substituted orunsubstituted alkoxy group, or hydroxyl; A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹;X is N or CH; R¹⁰ and R¹¹ are independently hydrogen, a substituted orunsubstituted alkyl group, or halogen; m is 3 or 4; wherein at least oneof R⁵, R¹⁰, or R¹¹ is a halogen or pharmaceutically acceptable salts orsolvates thereof; or d) wherein R¹ and R² are hydrogen; or R¹ is ahydrogen or a substituted or unsubstituted alkyl group when R² and R³are part of a heterocycle; R³ and R⁴ are independently chosen fromhydrogen, C₁₋₄alkyl, or R³, R⁴ and the carbon atom to which they areattached form a cyclopropyl ring, or R² and R³ together represent(CH₂)_(m) to form a saturated heterocycle; R⁵ is chosen from hydrogen,halogen, or a substituted or unsubstituted alkyl group; R⁶-R⁹ areindependently chosen from hydrogen, halogen, a substituted orunsubstituted alkyl group, a substituted or unsubstituted alkoxy group,or hydroxyl; A is CH₂CH₂, CH═CH, or CR¹⁰R¹¹; X is CH; R¹⁰ and R¹¹ areindependently hydrogen, a substituted or unsubstituted alkyl group, orhalogen; m is 3 or 4; or pharmaceutically acceptable salts or solvatesthereof.
 26. The compound of claim 25, wherein said R³ or R⁴ or both isC₁₋₄alkyl.
 27. A pharmaceutical composition comprising the compound ofclaim 25 and at least one vehicle.